Pancreatic cancer (PaCA) has the poorest prognosis amongst all major cancer types and will claim the lives of 37,000 Americans this year. Upon clinical presentation, most patients (80%) are diagnosed with inoperable pancreatic cancer. Tumor removal is rarely performed due to the proximity of critical blood and digestive vessels. Resection of primary PaCA tumors can prevent further metastasis and address primary tumor-induced complications such as impaired endocrine and exocrine function and pain. Our proposed approach makes use of a new enabling near infrared light- triggered drug release nanotechnology along with PaCA tumor priming. A clinical scenario might involve laparoscopy guidance (already used in PaCA) of a near infrared emitting optical fiber into the primary tumor to trigger drug release. This approach overcomes challenges with light penetration and will spare damage to critical pancreatic vessels. Although PaCA cells are sensitive to conventional chemotherapies, difficulty in treating the disease stems from poor tumor vascularization. Our preliminary data demonstrate that inhibition of the sonic hedgehog pathway can enhance vascularization and delivery of liposomal doxorubicin, leading to a delay in tumor progression in a hypovascular mouse PaCA model. Here, we aim to achieve complete tumor eradication by combining tumor priming with doxorubicin-loaded, light-sensitive porphysome (LS-porphysomes). Porphysomes are liposome-like particles formed from a porphyrin bilayer that gives rise to unique nanoscale photonic properties. We have developed LS-porphysomes that stably retain entrapped drug in serum; yet completely rapidly release their contents upon near infrared light exposure. The release mechanism, which involves doping porphyrin bilayers with high transition temperature lipids, is based on a novel nanoscale heating phenomenon unique to porphysomes. This project has three specific aims: Specific Aim 1: Optimize serum-stable, biocompatible drug-loaded, LS-porphysomes: We will optimize LS-porphysome chemistry and formulation to create a new type of robust, controlled release nanosystem and examine LS-porphysome in vivo stability and toxicity. Specific Aim 2: Develop an optimal PaCA tumor deposition strategy for LS-porphysomes: We use photoacoustic tomography to non-invasively determine how sonic hedgehog priming conditions enhance tumor vascularization and LS-porphysome delivery to both tumor microvessels and parenchyma. Specific Aim 3: Test the efficacy of doxorubicin release in PaCA tumors using LS-porphysomes: LS-porphysomes enable drug release while circulating levels are high (immediately following injection) but are also stable enough to also enable later, post-extravasation release. We will compare these approaches in distribution and survival studies and confirm that pancreatic function is not negatively affected.